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- PDB-7f0i: phosphodiesterase-9A in complex with inhibitor 4b -

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Basic information

Entry
Database: PDB / ID: 7f0i
Titlephosphodiesterase-9A in complex with inhibitor 4b
ComponentsIsoform PDE9A2 of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
KeywordsHYDROLASE/INHIBITOR / HYDROLASE-Inhibitor complex
Function / homology
Function and homology information


cGMP metabolic process / 3',5'-cyclic-GMP phosphodiesterase / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / cGMP effects / 3',5'-cyclic-GMP phosphodiesterase activity / cGMP-mediated signaling / 3',5'-cyclic-nucleotide phosphodiesterase activity / sarcolemma / ruffle membrane ...cGMP metabolic process / 3',5'-cyclic-GMP phosphodiesterase / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / cGMP effects / 3',5'-cyclic-GMP phosphodiesterase activity / cGMP-mediated signaling / 3',5'-cyclic-nucleotide phosphodiesterase activity / sarcolemma / ruffle membrane / perikaryon / perinuclear region of cytoplasm / Golgi apparatus / endoplasmic reticulum / signal transduction / nucleoplasm / identical protein binding / metal ion binding / plasma membrane / cytosol
Similarity search - Function
3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase domain signature. / 3'5'-cyclic nucleotide phosphodiesterase domain profile. / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain
Similarity search - Domain/homology
Chem-06A / High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.70000890032 Å
AuthorsWu, Y. / Huang, Y.Y. / Luo, H.B.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21977127 and 21877134 China
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of Potent Phosphodiesterase-9 Inhibitors for the Treatment of Hepatic Fibrosis
Authors: Wu, Y. / Wang, Q. / Jiang, M.Y. / Huang, Y.Y. / Zhu, Z. / Han, C. / Tian, Y.J. / Zhang, B. / Luo, H.B.
History
DepositionJun 4, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 13, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform PDE9A2 of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
B: Isoform PDE9A2 of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,5348
Polymers123,5782
Non-polymers9566
Water2,090116
1
A: Isoform PDE9A2 of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,2674
Polymers61,7891
Non-polymers4783
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-32 kcal/mol
Surface area14420 Å2
MethodPISA
2
B: Isoform PDE9A2 of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,2674
Polymers61,7891
Non-polymers4783
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-32 kcal/mol
Surface area14160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.467, 103.467, 268.921
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

#1: Protein Isoform PDE9A2 of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A


Mass: 61789.078 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE9A / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: O76083-2, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-06A / 1-cyclopentyl-6-[[(2R)-1-(6-fluoranyl-2-azaspiro[3.3]heptan-2-yl)-1-oxidanylidene-propan-2-yl]amino]-5H-pyrazolo[3,4-d]pyrimidin-4-one


Mass: 388.439 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H25FN6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 116 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Sequence detailsTHIS SEQUENCE CORRESPONDS TO THE ISOFORM PDE9A2 FOUND IN UNP O76083.

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.91 Å3/Da / Density % sol: 57.76 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 3.0M Na formate, 0.1M HEPES (pH 7.5), 5% xylitol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54056 Å
DetectorType: RIGAKU HyPix-3000 / Detector: PIXEL / Date: Apr 12, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54056 Å / Relative weight: 1
ReflectionResolution: 2.7→23.5321 Å / Num. obs: 40355 / % possible obs: 98.4 % / Redundancy: 8.9 % / Biso Wilson estimate: 34.5489656212 Å2 / Rmerge(I) obs: 0.14 / Net I/σ(I): 21.4
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 9.7 % / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 5 / Num. unique obs: 4030 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC1.10_2155refinement
CrysalisProdata reduction
CrysalisProdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6A3N

6a3n


Resolution: 2.70000890032→23.5320777477 Å / SU ML: 0.504562992188 / Cross valid method: NONE / σ(F): 2.02616478662 / Phase error: 32.4962839839
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.333696578959 1961 4.85949348268 %
Rwork0.270818453015 38393 -
obs0.27379037353 40354 98.4003901487 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.0805812221 Å2
Refinement stepCycle: LAST / Resolution: 2.70000890032→23.5320777477 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5192 0 60 116 5368
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0102115497225388
X-RAY DIFFRACTIONf_angle_d1.211221336647311
X-RAY DIFFRACTIONf_chiral_restr0.0575645343453788
X-RAY DIFFRACTIONf_plane_restr0.00768188660648965
X-RAY DIFFRACTIONf_dihedral_angle_d23.54962453422059
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.701-2.76740.3650518170391390.3058927784632716X-RAY DIFFRACTION100
2.7674-2.84210.3644976301511400.3084373594342735X-RAY DIFFRACTION100
2.8421-2.92560.378974158051340.3085807258862743X-RAY DIFFRACTION100
2.9256-3.01990.4287743703941480.3287241510972716X-RAY DIFFRACTION100
3.0199-3.12760.3782768874111450.3150269979842765X-RAY DIFFRACTION99.9656475438
3.1276-3.25250.3979602581311190.3071789166512761X-RAY DIFFRACTION99.6539792388
3.2525-3.40010.367283242431670.2859625270312713X-RAY DIFFRACTION99.7575337721
3.4001-3.57880.35516964341410.2905967505382749X-RAY DIFFRACTION99.2104359767
3.5788-3.80210.3402961822231570.2606639131972717X-RAY DIFFRACTION98.8308115543
3.8021-4.09430.3269074146061320.2518247148482713X-RAY DIFFRACTION97.4982864976
4.0943-4.50370.2791124665711240.2504745228362750X-RAY DIFFRACTION97.1602434077
4.5037-5.14940.2762525865291390.2351144199432714X-RAY DIFFRACTION96.2225969646
5.1494-6.46540.3023929379761350.2508800628382780X-RAY DIFFRACTION96.8116904683
6.4654-23.5310.2882205094531410.2385507372672821X-RAY DIFFRACTION93.2032724984

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